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Open AccessArticle

Expression of Immune System-Related Membrane Receptors CD40, RANK, BAFFR and LTβR is Associated with Clinical Outcome of Operated Non-Small-Cell Lung Cancer Patients

1
Molecular Oncology Laboratory, Division of Oncology, Department of Medicine, Medical School, University of Patras, 26504 Patras, Greece
2
Department of Cardiothoracic Surgery, Medical School, University of Patras, 26504 Patras, Greece
3
Department of Pathology, Medical School, University of Patras, 26504 Patras, Greece
4
Institute of Biomedical Engineering, Imperial College London, London SW7 2AZ, UK
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2019, 8(5), 741; https://doi.org/10.3390/jcm8050741
Received: 23 April 2019 / Revised: 7 May 2019 / Accepted: 20 May 2019 / Published: 24 May 2019
An increasing number of studies implicates the NF-κB (Nuclear Factor of kappa light chain gene enhancer in B cells) alternative pathway in non-small-cell lung cancer (NSCLC). We assessed the clinical significance of CD40 (Tumor necrosis factor receptor superfamily member 5, TNFRSF5), BAFFR (B-cell activating factor receptor), RANK (Receptor activator of NF-κB) and LTβR (lymphotoxin β receptor) receptors, which activate the alternative pathway of NF-κB, in NSCLC. Evaluation of CD40, BAFFR, RANK and LTβR expression was performed based on the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets, while protein expression was assessed by immunohistochemistry in specimens from 119 operated NSCLC patients. CD40 gene overexpression was correlated with improved five-year overall survival (OS) (p < 0.001), while increased BAFFR and LTβR mRNA levels were associated with worse OS in patients with adenocarcinomas (p < 0.001 and p < 0.001, respectively). Similarly, patients with adenocarcinomas exhibited a negative correlation between membranous BAFFR protein expression in carcinoma cells and three- and five-year survival (p = 0.021; HR, 4.977 and p = 0.030; HR, 3.358, respectively) as well as between BAFFR protein overexpression in cancer-associated fibroblasts (CAFs) and two-year survival (p = 0.036; HR, 1.983). Patients with increased LTβR nuclear protein staining or stage II patients with lower cytoplasmic LTβR protein expression had worse five-year OS (p = 0.039 and p = 0.008, respectively). Moreover, CD40 protein expression in tumor infiltrating lymphocytes (TILs) and CAFs was positively associated with metastatic spread while BAFFR protein expression in CAFs was negatively associated with bone metastasis (p = 0.041). Our data suggests that CD40, BAFFR, RANK and LTβR play an important role in NSCLC and further supports the role of NF-κB alternative pathway in NSCLC. View Full-Text
Keywords: CD40; BAFFR; RANK; LTβR; NSCLC; prognosis; survival; lung cancer; expression; protein; mRNA CD40; BAFFR; RANK; LTβR; NSCLC; prognosis; survival; lung cancer; expression; protein; mRNA
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Dimitrakopoulos, F.-I.D.; Kottorou, A.E.; Antonacopoulou, A.G.; Panagopoulos, N.; Scopa, C.; Kalofonou, M.; Dougenis, D.; Koutras, A.; Makatsoris, T.; Tzelepi, V.; Kalofonos, H.P. Expression of Immune System-Related Membrane Receptors CD40, RANK, BAFFR and LTβR is Associated with Clinical Outcome of Operated Non-Small-Cell Lung Cancer Patients. J. Clin. Med. 2019, 8, 741.

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